Original articles
Wanrong Yi, Mei-Juan Tu, Zhenzhen Liu, Chao Zhang, Neelu Batra, Ai-Xi Yu, Ai-Ming Yu. Bioengineered miR-328-3p modulates GLUT1-mediated glucose uptake and metabolism to exert synergistic antiproliferative effects with chemotherapeutics[J]. Acta Pharmaceutica Sinica B, 2020, 10(1): 159-170

Bioengineered miR-328-3p modulates GLUT1-mediated glucose uptake and metabolism to exert synergistic antiproliferative effects with chemotherapeutics
Wanrong Yia,b, Mei-Juan Tub, Zhenzhen Liub, Chao Zhangb, Neelu Batrab, Ai-Xi Yua, Ai-Ming Yub
a Department of Orthopaedic Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan 430072, China;
b Department of Biochemistry & Molecular Medicine, UC Davis School of Medicine, Sacramento 95817, CA, USA
Abstract:
MicroRNAs (miRNAs or miRs) are small noncoding RNAs derived from genome to control target gene expression. Recently we have developed a novel platform permitting high-yield production of bioengineered miRNA agents (BERA). This study is to produce and utilize novel fully-humanized BERA/miR-328-3p molecule (hBERA/miR-328) to delineate the role of miR-328-3p in controlling nutrient uptake essential for cell metabolism. We first demonstrated successful high-level expression of hBERA/miR-328 in bacteria and purification to high degree of homogeneity (>98%). Biologic miR-328-3p prodrug was selectively processed to miR-328-3p to suppress the growth of highly proliferative human osteosarcoma (OS) cells. Besides glucose transporter protein type 1, gene symbol solute carrier family 2 member 1 (GLUT1/SLC2A1), we identified and verified large neutral amino acid transporter 1, gene symbol solute carrier family 7 member 5 (LAT1/SLC7A5) as a direct target for miR-328-3p. While reduction of LAT1 protein levels by miR-328-3p did not alter homeostasis of amino acids within OS cells, suppression of GLUT1 led to a significantly lower glucose uptake and decline in intracellular levels of glucose and glycolytic metabolite lactate. Moreover, combination treatment with hBERA/miR-328 and cisplatin or doxorubicin exerted a strong synergism in the inhibition of OS cell proliferation. These findings support the utility of novel bioengineered RNA molecules and establish an important role of miR-328-3p in the control of nutrient transport and homeostasis behind cancer metabolism.
Key words:    Bioengineered RNA    MiR-328    LAT1    GLUT1    Chemosensitivity    Cancer   
Received: 2019-06-26     Revised: 2019-08-16
DOI: 10.1016/j.apsb.2019.11.001
Funds: Ai-Xi Yu is supported by Hubei Province Scientific and Technological Innovation Key Project (No. 2019ACA136, China). AiMing Yu is supported by National Institute of General Medical Sciences grant (No. R01GM113888) and National Cancer Institute grant (No. R01CA225958), National Institutes of Health (USA). Wanrong Yi is supported by a fellowship from the Chinese Scholarship Council (No. 201706270162, China). The authors also appreciate the access to the Molecular Pharmacology Shared Resources funded by the UC Davis Comprehensive Cancer Center Support Grant awarded by the National Cancer Institute grant (P30CA093373, USA).
Corresponding author: Ai-Xi Yu, Ai-Ming Yu     Email:yuaixi@whu.edu.cn;aimyu@ucdavis.edu
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Wanrong Yi
Mei-Juan Tu
Zhenzhen Liu
Chao Zhang
Neelu Batra
Ai-Xi Yu
Ai-Ming Yu

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